Membrane disruption

Hypothermia—Indirect cryodestruction Metabolic uncoupling Energy deprivation Ionic imbalance Disruption of acid-base balance Waste accumulation Membrane phase transitions Cytoskeletal disassembly Frozen State—Direct cryodestruction Water solidification Hyperosmolality Cell-volume disruption Protein denaturation Tissue shearing Intracellular-ice propagation Membrane disruption Microvascular Thawed State Direct effects... 

There has been considerable discussion regarding the mode of action of the sea cucumber and starfish saponins. Both the triterpene and steroidal glycosides inhibit both Na/K ATPase and Ca/Mg ATPase 06) possibly as a result of their aglycone structures. However, their detergent properties cause membrane disruption which will influence the activity of membrane-bound enzymes such as the ATPases. In investigating the actions of saponins on multilamellar liposomes, it was found that cholesterol serves as the binding site for such saponins and that cholesterol-free lip-somes are not lysed by saponins 107). 

Cytoplasmic membrane Polymyxins Polyenes Imidazoles and triazoles Naftidine Disrupt bacterial membranes Disrupt fungal membranes Inhibit ergosterol synthesis Inhibits ergosterol synthesis Bind to LPS and phospholipids Bind preferentially to ergosterol Pathway not in mammalian cells Pathway not in mammalian cells... 

Other systems like electroporation have no lipids that might help in membrane sealing or fusion for direct transfer of the nucleic acid across membranes they have to generate transient pores, a process where efficiency is usually directly correlated with membrane destruction and cytotoxicity. Alternatively, like for the majority of polymer-based polyplexes, cellular uptake proceeds by clathrin- or caveolin-dependent and related endocytic pathways [152-156]. The polyplexes end up inside endosomes, and the membrane disruption happens in intracellular vesicles. It is noteworthy that several observed uptake processes may not be functional in delivery of bioactive material. Subsequent intracellular obstacles may render a specific pathway into a dead end [151, 154, 156]. With time, endosomal vesicles become slightly acidic (pH 5-6) and finally fuse with and mature into lysosomes. Therefore, polyplexes have to escape into the cytosol to avoid the nucleic acid-degrading lysosomal environment, and to deliver the therapeutic nucleic acid to the active site. Either the carrier polymer or a conjugated endosomolytic domain has to mediate this process [157], which involves local lipid membrane perturbation. Such a lipid membrane interaction could be a toxic event if occurring at the cell surface or mitochondrial membrane. Thus, polymers that show an endosome-specific membrane activity are favorable. 

Bulmus V, Woodward M, Lin L, Murthy N, Stayton P, Hoffman A (2003) A new pH-responsive and glutathione-reactive, endosomal membrane-disruptive polymeric carrier for intracellular delivery of biomolecular drugs. J Control Release 93 105-120... 

Wang XL, Xu R, Lu ZR (2009) A peptide-targeted delivery system with pH-sensitive amphiphilic cell membrane disruption for efficient receptor-mediated siRNA delivery. J Control Release 134 207-213... 

Synthetic poly(alkylacrylic acid) [141, 142] and poly(alkylacrylic acid-co-alkyl acrylate) [143, 144] also have pH-dependent, membrane-disruptive properties. 

Chen R, Yue Z, Eccleston ME et al (2005) Modulation of cell membrane disruption by pH-responsive pseudo-peptides through grafting with hydrophilic side chains. J Control Release 108 63-72... 

Murthy N, Robichaud JR, Tirrell DA et al (1999) The design and synthesis of polymers for eukaryotic membrane disruption. J Control Release 61 137-143... 

Kusonwiriyawong C, van de Wetering P, Hubbell JA et al (2003) Evaluation of pH-dependent membrane-disruptive properties of poly(acrylic acid) derived polymers. Eur J Pharm Biopharm 56 237-246... 

Some attempts have been made to rationally increase the efficiency of endosomal escape. One such avenue entails the incorporation of selected hydrophobic (viral) peptides into the gene delivery systems. Many viruses naturally enter animal cells via receptor-mediated endocytosis. These viruses have evolved efficient means of endosomal escape, usually relying upon membrane-disrupting peptides derived from the viral coat proteins. 

Demuro, A., Mina, E., Kayed, R., Milton, S. C., Parker, I., and Glabe, C. G. (2005). Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers./. Biol. Chem. 280, 17294—17300. 

Fullerene showed antibacterial activity, which can be attributed to different interactions of C60 with biomolecules (Da Ros et al., 1996). In fact, there is a possibility to induce cell membrane disruption. The fullerene sphere seems not really adaptable to planar cellular surface, but for sure the hydrophobic surface can easily interact with membrane lipids and intercalate into them. However, it has been demonstrated that fullerene derivatives can inhibit bacterial growth by unpairing the respiratory chain. There is, first, a decrease of oxygen uptake at low fullerene derivative concentration, and then an increase of oxygen uptake, which is followed by an enhancement of hydrogen peroxide production. The higher concentration of C60 seems to produce an electron leak from the bacterial respiratory chain (Mashino et al., 2003). 

The Meyer-Overton hypothesis proposed that once a sufficient number of anaesthetic molecules were dissolved in the lipid membranes of cells within the central nervous system, anaesthesia would result by a mechanism of membrane disruption. While an interesting observation, there are several exceptions to the rule that make it insufficient to account fully for the mechanism of anaesthesia. 

Several different modes of membrane disruption have been proposed as possible mechanisms of action for peptide antibiotics in general [2,5] ... 

Biochemical- -cellular Detoxification Membrane disruption Adaptation of organism Reduction In condition of... 

According to Helenius and Simons (30) solubilization of the membrane is preceded by saturation of the bilayer with surfactant. Certainly critical surfactant/phospholipid ratios must be attained before membrane disruption occurs. 

Keukens EAJ et al (1995) Molecular basis of glycoalkaloid induced membrane disruption. Biochim Biophys Acta 1240 216... 

The amount of total enzymatic activity that becomes manifest only after disruption of membranous barriers between enzyme and substrate or upon removal of some otherwise inhibitory factor. Membrane disruption is often achieved by treatment with detergent to solubihze the enzyme. One example is the so-called microsomal glucose-6-phosphatase, an enzymatic activity that is located in the lumen of the endoplasmic reticulum but becomes trapped as a latent activity in microsome vesicles upon mechanical disruption of cells. 

LIPID ACTIVATION MEMBRANE TRANSPORT Membrane disruption,... 

Roddiek, J. G., Weissenberg, M., Leonard, A. L. (2001). Membrane disruption and enzyme inhibition by naturally-oeeurring and modified ehaeotriose-eontaining Solanum steroidal glycoalkaloids. Phytochemistry, 56,603-610. 

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